Subconjunctival delivery of p75NTR antagonists reduces the inflammatory, vascular, and neurodegenerative pathologies of diabetic retinopathy

The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. METHODS. We compared the pharmacokinetics of a single 40 lg subconjunctival (SCJ) depot to the reported effective 5 lg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. RESULTS. The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. CONCLUSIONS. Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.Fil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Nedev, Hinyu. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Sarunic, Marinko V.. University Fraser Simon; CanadáFil: Jian, Yifan. University Fraser Simon; CanadáFil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canad

Analysis of the impact of impulse noise in digital subscriber line systems

In recent years, Digital subscriber line (DSL) technology has been gaining popularity as a high speed network access technology, capable of the delivery of multimedia services. A major impairment for DSL is impulse noise in the telephone line. However, evaluating the data errors caused by this noise is not trivial due to its complex statistical nature, which until recently had not been well understood, and the complicated error mitigation and framing techniques used in DSL systems. This thesis presents a novel analysis of the impact of impulse noise and the DSL framing parameters on transmission errors, building on a recently proposed impulse noise model. It focuses on errors at higher protocol layers, such as asynchronous transfer mode (ATM), in the most widely used DSL version, namely Asymmetric DSL (ADSL). The impulse noise is characterised statistically through its amplitudes, duration, inter-arrival times, and frequency spectrum, using the British Telecom / University of Edinburgh / Deutsche Telekom (BT/UE/DT) model. This model is broadband, considers both the time and the frequency domains, and accounts for the impulse clustering. It is based on recent measurements in two different telephone networks (the UK and Germany) and therefore is the most complete model available to date and suited for DSL analysis. A new statistical analysis of impulse noise spectra from DT measurements shows that impulse spectra can be modelled with three spectral components with similar bandwidth statistical distributions. Also, a novel distribution of the impulse powers is derived from the impulse amplitude statistics. The performance of a generic ADSL modem is investigated in an impulse noise and crosstalk environment for different bit rates and framing parameters. ATM cell and ADSL frame error rates, and subjective MPEG2 video quality are used as performance metrics. A new modification of a bit loading algorithm is developed to enable stable convergence of the algorithm with trellis coding and restricted subtone constellation size. It is shown that while interleaving brings improvement if set at its maximum depth, at intermediate depths it actually worsens the performance of all considered metrics in comparison with no interleaving. No such performance degradation is caused by combining several symbols in a forward error correction (FEC) codeword, but this burst error mitigation technique is only viable at low bit rates. Performance improvement can also be achieved by increasing the strength of FEC, especially if combined with interleaving. In contrast, trellis coding is ineffective against the long impulse noise error bursts. Alien as opposed to kindred crosstalk degrades the error rates and this is an important issue in an unbundled network environment. It is also argued that error free data units is a better performance measure from a user perspective than the commonly used error free seconds. The impact of impulse noise on the errors in DSL systems has also been considered analytically. A new Bernoulli-Weibull impulse noise model at symbol level is proposed and it is shown that other models which assume Gaussian distributed impulse amplitudes or Rayleigh distributed impulse powers give overly optimistic error estimates in DSL systems. A novel bivariate extension of the Weibull impulse amplitudes is introduced to enable the analysis of orthogonal signals. Since an exact closed-form expression for the symbol error probability of multi-carrierQAM assuming Bernoulli-Weibull noise model does not exist, this problem has been solved numerically. Multi-carrier QAM is shown to perform better at high signal-to-noise ratio (SNR), but worse at low SNR than single carrier QAM, in both cases because of the spreading of noise power between subcarriers. Analytical expressions for errors up to frame level in the specific case of ADSL are then derived from the impulse noise model, with good agreement with simulation results. The Bernoulli-Weibull model is applied to study the errors in single-pair highspeed DSL (SHDSL). The performance of ADSL is found to be better when the burst error mitigation techniques are used, but SHDSL has advantages if low bit error rate and low latency are required

Continuous selections of multivalued mappings

This survey covers in our opinion the most important results in the theory of continuous selections of multivalued mappings (approximately) from 2002 through 2012. It extends and continues our previous such survey which appeared in Recent Progress in General Topology, II, which was published in 2002. In comparison, our present survey considers more restricted and specific areas of mathematics. Note that we do not consider the theory of selectors (i.e. continuous choices of elements from subsets of topological spaces) since this topics is covered by another survey in this volume

Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors

Glial cell line?derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor ?1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET?GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.Peer reviewe

Fast optoelectric printing of plasmonic nanoparticles into tailored circuits

Plasmonic nanoparticles are able to control light at nanometre-scale by coupling electromagnetic fields to the oscillations of free electrons in metals. Deposition of such nanoparticles onto substrates with tailored patterns is essential, for example, in fabricating plasmonic structures for enhanced sensing. This work presents an innovative micro-patterning technique, based on optoelectic printing, for fast and straightforward fabrication of curve-shaped circuits of plasmonic nanoparticles deposited onto a transparent electrode often used in optoelectronics, liquid crystal displays, touch screens, etc. We experimentally demonstrate that this kind of plasmonic structure, printed by using silver nanoparticles of 40 nm, works as a plasmonic enhanced optical device allowing for polarized-color-tunable light scattering in the visible. These findings have potential applications in biosensing and fabrication of future optoelectronic devices combining the benefits of plasmonic sensing and the functionality of transparent electrodes

Raft-Dependent Endocytosis of Autocrine Motility Factor/Phosphoglucose Isomerase: A Potential Drug Delivery Route for Tumor Cells

Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) is the extracellular ligand for the gp78/AMFR receptor overexpressed in a variety of human cancers. We showed previously that raft-dependent internalization of AMF/PGI is elevated in metastatic MDA-435 cells, but not metastatic, caveolin-1-expressing MDA-231 cells, relative to non-metastatic MCF7 and dysplastic MCF10A cells suggesting that it might represent a tumor cell-specific endocytic pathway.Similarly, using flow cytometry, we demonstrate that raft-dependent endocytosis of AMF/PGI is increased in metastatic HT29 cancer cells expressing low levels of caveolin-1 relative to metastatic, caveolin-1-expressing, HCT116 colon cells and non-metastatic Caco-2 cells. Therefore, we exploited the raft-dependent internalization of AMF/PGI as a potential tumor-cell specific targeting mechanism. We synthesized an AMF/PGI-paclitaxel conjugate and found it to be as efficient as free paclitaxel in inducing cytotoxicity and apoptosis in tumor cells that readily internalize AMF/PGI compared to tumor cells that poorly internalize AMF/PGI. Murine K1735-M1 and B16-F1 melanoma cells internalize FITC-conjugated AMF/PGI and are acutely sensitive to AMF/PGI-paclitaxel mediated cytotoxicity in vitro. Moreover, following in vivo intratumoral injection, FITC-conjugated AMF/PGI is internalized in K1735-M1 tumors. Intratumoral injection of AMF/PGI-paclitaxel induced significantly higher tumor regression compared to free paclitaxel, even in B16-F1 cells, known to be resistant to taxol treatment. Treatment with AMF/PGI-paclitaxel significantly prolonged the median survival time of tumor bearing mice. Free AMF/PGI exhibited a pro-survival role, reducing the cytotoxic effect of both AMF/PGI-paclitaxel and free paclitaxel suggesting that AMF/PGI-paclitaxel targets a pathway associated with resistance to chemotherapeutic agents. AMF/PGI-FITC uptake by normal murine spleen and thymus cells was negligible both in vitro and following intravenous injection in vivo where AMF/PGI-FITC was selectively internalized by subcutaneous B16-F1 tumor cells.The raft-dependent endocytosis of AMF/PGI may therefore represent a tumor cell specific endocytic pathway of potential value for drug delivery to tumor cells

Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFR alpha 1

Glial cell line-derived neurotrophic factor (GDNF) binds the GFR alpha 1 receptor, and the GDNF-GFR alpha 1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFR alpha 1-RET signaling complex, agents that bind and activate RET directly and independently of GFR alpha 1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFR alpha 1 coexpression. However, RET activation by these ligands is constrained by GFR alpha 1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor a, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.Peer reviewe

Search for η\eta-mesic nuclei in recoil-free transfer reaction

We have studied the reaction $p+{^{27}Al}\to {^3{He}}+p+\pi^-+X$ at recoil-free kinematics. An $\eta$ meson possibly produced in this reaction would be thus almost at rest in the laboratory system and could therefore be bound with high probability, if nuclear $\eta$ states exist. The decay of such a state through the $N^*(1535)$ resonance would lead to a proton-$\pi^-$ pair emitted in opposite directions. For these conditions we find some indication of such a bound state. An upper limit of $\approx$ 0.5 nb is found.Comment: 3 figure

A precision determination of the mass of the η\eta meson

Several processes of meson production in proton-deuteron collisions have been measured simultaneously using a calibrated magnetic spectrograph. Among these processes, the $\eta$ meson is seen clearly as a sharp missing--mass peak on a slowly varying background in the $p+d\to ^3\textrm{He} +X$ reaction. Knowing the kinematics of the other reactions with well determined masses, it is possible to deduce a precise mass for the $\eta$ meson. The final result, $m(\eta)=547.311\pm 0.028 \textrm{(stat)} \pm 0.032 \textrm{(syst) MeV/c}^2$, is significantly lower than that found by the recent NA48 measurement, though it is consistent with values obtained in earlier counter experiments.Comment: 10 pages, 6 figures, Fig. 3 change